tbuckley/cabot-search huggingface dataset:
DIPG-10. A Phase I trial of panobinostat following radiation therapy in children with diffuse intrinsic pontine glioma (DIPG) or H3K27M-mutated thalamic diffuse midline glioma (DMG): Report from the Pediatric Brain Tumor Consortium (PBTC-047)
Authors: Michelle Monje, Tabitha Cooney, John Glod, Jie Huang, Patricia Baxter, Anna Vinitsky, Lindsay Kilburn, Nathan J Robison, Cody J Peer, William D Figg, Maryam Fouladi, Jason Fangusaro, Arzu Onar-Thomas, Ira J Dunkel, Katherine E Warren
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Panobinostat is an oral HDAC inhibitor with pre-clinical activity against DIPG. The phase I study in children with progressive DIPG (stratum 1) defined the maximum-tolerated dose (MTD) as 10 mg/m2 administered 3x/week, 3 weeks on/1 week off. Herein, we report results of stratum 2, involving children with non-progressive DIPG/DMG using an alternative schedule. Primary objectives were to describe the toxicity profile and define the MTD; secondary objectives were to describe progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: Patients with non-progressive DIPG or H3K27M-mutated thalamic DMG were eligible &amp;gt;14 days following standard radiation therapy only. Panobinostat was given every other day, 3x/week, on alternate weeks. Patients who received at least one dose of panobinostat were evaluable for toxicity. Four dose levels (DL) were evaluated: DL1 (16mg/m2/dose), DL2 (22 mg/m2/dose), DL3 (28 mg/m2/dose) and DL4 (36 mg/m2/dose). Dose escalation was determined by a continuous reassessment method. Correlative studies included pharmacokinetics obtained on course 1, day 1, and day 3 prior to subsequent dosing. RESULTS: Thirty-four eligible patients (median age, 7.6 [3-16] years) were enrolled with 29 evaluable for dose finding; DL1, n=3; DL2, n=10; DL3, n=11; DL4, n=5. The primary toxicities were myelosuppression and gastrointestinal. Eight DLTs occurred: DL2, Grade 3 thrombocytopenia (n=1); DL3, Grade 4 neutropenia (n=3), Grade 4 neutropenia and Grade 4 thrombocytopenia, (n=1); DL4, Grade 2 nausea (n=1), Grade 3 increased ALT (n=1), Grade 4 thrombocytopenia (n=1). Median PFS from drug initiation was 4.4 (1-11.2) months; median OS from diagnosis was 11.7 (4.5-25) months. These did not significantly differ from the PBTC historical cohort (PFS, p-value 0.4967; OS, p-value 0.6457). CONCLUSION: The MTD of panobinostat administered on this schedule to children with non-progressive DIPG/DMG is 22 mg/m2/dose. The primary DLT was myelosuppression. There was no significant improvement in PFS or OS in this cohort.
HGG-25. Targeting KLF5 reduces tumorigenic phenotype in a murine glioblastoma (GBM) model
Authors: Tamara Abou-Antoun, Najla Kfoury, Lihua Yang, Nicole Warrington, Xuhua Chen, India Reiss, Michael Wilkinson, Robi Mitra, Josh Rubin
Journal: Neuro-Oncology (2022)

Abstract Sex differences are evident in the incidence, therapeutic response and survival of patients with various cancers including the most common, aggressive and incurable GBM. We generated a murine GBM model of male and female astrocytes with dual loss of NF1 and P53 that yielded a sex-biased transformation of the astrocytes with male cells being significantly more tumorigenic and therapeutically resistant compared to female cells. In our current work, we aimed to delineate the molecular mechanisms driving this sex-biased tumorigenic phenotype in order to deliver therapies that are more effective to patients with GBM. We examined the inhibition of KLF5 on tumorigenic phenotypes using cellular bio-functional assays. We used barcoded transposon calling cards to determine the genomic localization of KLF5 and the differentially induced gene expression in male versus female GBM cells. Chemical inhibition or shRNA knock-down of KLF5 significantly reduced proliferation, migration, clonogenic stem-cell frequency and survival, but increase apoptosis in male and female GBM cells. Interestingly, male, but not female, GBM cells exhibited an increased migratory phenotype after radiation that inhibition of KLF5 significantly reduced. Moreover, KLF5 inhibition significantly reduced the protein expression of tumorigenic PDGFRB, AKT, ERK and the stem marker Sox-2. Transposon calling cards mapped unique KLF5 genomic localization in male versus female GBM cells with significantly differential gene expression profiles between the two. The top genes induced by KLF5 in male cells were primarily affiliated with poorer prognosis and reduced survival, whereas in female cells they were affiliated with better prognosis and improved survival in patients with cancer. Our findings provide a promising exploratory avenue for KLF5 as a therapeutic target in GBM and warrants further investigation in order to delineate the precise molecular mechanisms driving this antitumor response so that targeted therapy would be more effective taking into consideration the sex-differences in patients with GBM.
Impact of patient and lifestyle factors in patients with stage III &amp; IV renal cancer: A Danish nationwide study
Authors: F. Ebbestad, L. Geertsen, N. Nadler, S.S. Axelsen, T.A. Horsbøll, S.O. Dalton, J. Christensen, F. Donskov, L. Lund, N.H. Azawi
Journal: European Urology (2022)
Trends in Annual Sales and Pack Price of Cigarettes in the US, 2015-2021
Authors: Fatma Romeh M. Ali, Elizabeth L. Seaman, Barbara Schillo, Donna Vallone
Journal: JAMA Network Open (2022)

Cigarette sales data were licensed from IRi, which records brick-and-mortar retail scanner sales but not online sales (eMethods in the Supplement).Sales of 20-cigarette packs 5 were aggregated annually from February 1, 2015, to December 26, 2021, for the continental United States and Washington, DC.Trends in total pack sales, menthol share from total pack sales, total dollar sales, and pack price were assessed using Joinpoint Regression Program, version 4.9.0.0 (National Cancer Institute).Average annual percentage change (AAPC) and 95% CIs were calculated.Statistical significance was defined as 2-tailed P < .05.This cross-sectional study followed the STROBE reporting guideline.This study was approved by a central institutional review board, Advarra, which determined that institutional review board oversight was not required because it did not involve human participants research. ResultsFrom February 1, 2015, to December 26, 2021, the annual number of cigarette packs sold decreased by 27.2%, from 12.5 billion packs to 9.1 billion packs (AAPC, -5.3%; 95% CI, -6.6% to -3.9%) (Figure 1A).During this period, dollar sales decreased overall by 6.0%, from $69.8 billion to $65.6 billion (AAPC, -1.2%; 95% CI, -2.0% to -0.3%) (Figure 1B), while prices increased by 29.5%, from $5.57 to $7.22 per pack (AAPC, 4.3%; 95% CI, 4.1% to 4.6%) (Figure 2).Menthol cigarettes accounted for 33.0% of total sales in 2021; there was no significant change in this percentage from 2015 to 2021.From January 26, 2020, to December 26, 2021, annual cigarette pack sales decreased by 7.6% (9.8 billion to 9.1 billion packs); dollar sales decreased by 1.4% ($66.5 billion to $65.6 billion), while prices increased by 6.8% ($6.76 to $7.22 per pack).Menthol share remained stable at 33.0%.
Immunological markers and somatic mutations as predictors for therapy selection in metastatic renal cell carcinoma
Authors: V. Stuehler, L. Herrmann, S. Winter, R. Bohnert, A. Reustle, J. Hennenlotter, S. Rausch, A. Stenzl, M. Schwab, E. Schaeffeler, J. Bedke
Journal: European Urology (2022)
Endoscopic ultrasound-guided hepaticogastrostomy using a novel drill dilator
Authors: Masanori Yamada, Kazuo Hara, Shin Haba, Nobumasa Mizuno, Takamichi Kuwahara, Nozomi Okuno, Yasuhiro Kuraishi
Journal: Endoscopy (2022)

Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) is an alternative to endoscopic retrograde cholangiopancreatography when the latter has failed [1] [2] [3]. Using a 22-gauge needle, 0.018-inch guidewire, and forward-viewing EUS, EUS-HGS is easier and safer to perform [4]. However, in some cases fistula dilation is difficult, because a 0.018-inch guidewire is relatively soft. Recently, we used a novel drill dilator (Tornus ES, Asahi Intecc) for EUS-HGS in a difficult case of this kind ([Fig. 1]). Here, we describe technical tips for fistula dilation using this tool.
MEDB-43. Development of a bioinformatics pipeline for identification of differential DNA methylation events associated with medulloblastoma relapse
Authors: Christopher Kui, Stacey Richardson, Edward C Schwalbe, Dean Thompson, Claire Keeling, Gordon Strathdee, Christelle Dufour, Simon Bailey, Vijay Ramaswamy, Steven C Clifford, Rebecca M Hill
Journal: Neuro-Oncology (2022)

Abstract Relapsed medulloblastoma (rMB) is treatment-resistant and fatal in ~95% of cases. The epigenetic features of rMB, and any role as drivers of disease relapse/treatment-resistance have yet to be investigated. We therefore developed a pipeline to identify differentially methylated CpGs (DM-CpGs) and regions (DMRs) in a paired-rMB cohort. Our paired-rMB cohort (n=61, relapsed tumours matched with diagnosis counterparts) with available Illumina Methylation 450K/850K microarray data was processed in R-Studio. The packages Limma and DMRcate were used to perform a paired differential methylation analysis on a filtered selection of array probes (n=335,767), identifying DM-CpGs and DMRs with a 5% FDR. DMRs were further retained if they had a maximum-Δβ of &amp;gt;0.2 and correlated with locus-specific gene expression in a separate paired DNA-methylation array/RNA-seq cohort from medulloblastoma diagnosis samples (n=202). Finally, we created univariable Cox models to assess the prognostic potential of DM-CpGs/DMRs in an independent survival cohort of medulloblastoma diagnosis samples (n=498). Across the paired-rMB cohort, there were few significant differential methylation events initially identified at relapse (n=258 DM-CpGs, n=32 DMRs). Upon sub-analysis by molecular group, MBGroup4 (n=18 pairs) alone yielded significant findings (n=189 DM-CpGs, n=26 DMRs). Most changes involved hypermethylation events detected at relapse. Multiple DM-CpGs identified at relapse were prognostic for both overall and event-free survival when assessed in our independent cohort (n=22 whole cohort, n=13 Group 4, BH-adjusted p&amp;lt;0.05). When applying the DMR filters, only the MBGroup4 DMRs passed the Δβ filter (n=18/26), with few correlating with gene expression (n=2, p&amp;lt;0.001), and none demonstrating prognostic significance. This pipeline facilitates exploration of the clinical relevance of epigenome-wide changes in a paired-rMB cohort. We highlight the potential prognostic significance of DM-CpGs, and future work will explore the potential functional role of candidate-genes associated with our DMRs, as novel drivers of rMB.
The most common location for stricture after transurethral prostate surgery (TPS) is the bulbomembranous urethra: False!
Authors: M. Bandini, C. Yepes, P. Joshi, D. Naranjo, S. Bhadranavar, F. Montorsi, A. Salonia, A. Briganti, G. Barbagli, S. Kulkarni
Journal: European Urology (2022)
The mutational profile of ER-, PR+, HER2- metastatic breast cancer.
Authors: Neal A. Fischbach, Richard S.P. Huang, Maryam B. Lustberg, Maureen Pelletier, Lajos Pusztai, Smruthy Sivakumar, Ethan Sokol, Jeffrey S. Ross, Mia Alyce Levy
Journal: Journal of Clinical Oncology (2022)

1025 Background: ER-PR+Her2- breast cancer is a rare subtype occurring at approximately 1% of all breast carcinomas. Most of these cancers behave in an aggressive fashion with limited benefit from anti estrogen therapy, similar to triple negative breast cancer (TNBC). Better characterization of these tumors is needed for predicting clinical behavior, response to endocrine therapy, and eligibility for clinical trials. Here we sought to evaluate the mutational profile of a well curated set of ER-PR+HER2- metastatic breast cancers and compare to other receptor phenotypes. Methods: 2049 consecutive breast cancers submitted to Foundation Medicine for comprehensive genomic profiling (CGP) were included. ER, PR and HER2 expression were abstracted from submitted pathology reports. Cases without complete ER, PR and HER2 information in pathology reports were excluded. CGP was performed as previously described (Frampton, 2013). Results: Patient ages were similar across subgroups. Generally, ER-PR+HER2- tumors were rare (n = 23, 1.1%) and most similar to TNBC in their genomic profiles. These tumors harbored high rates of TP53 and BRCA1 alterations and low rates of PIK3CA, ESR1, and CDH1 alterations. Genomic loss of heterozygosity (gLOH) was similar in the ER-PR+HER2- and ER+PR+HER2-subtypes (8.18% and 8.66% respectively), and lower than TNBC (17.19%). Notably, a high rate of RB1 alterations were identified in the ER-PR+HER2- patients (13%, 3/23), numerically higher than the other subtypes. EGFR, MET, PTEN, CDKN2A and KRAS alterations were also observed at a higher frequency in ER-PR+Her2- cancers (8.7, 4.2, 39.1, 13.0 and 13.0% respectively) relative to the other subtypes. IO drug biomarkers including MSI, TMB and PD-L1 IHC were similar among the groups. Conclusions: The mutational profile for ER-PR+Her2- metastatic breast cancer more closely resembles TNBC than ER+ breast cancer. These data suggest molecular profiling may be a useful adjunct to optimize treatment strategies for this rare subset of cancers. Based on molecular characteristics, we recommend including ER-PR+Her2- patients in clinical trials for TNBC. Finally, genes including RB1, CKDN2A, PTEN, EGFR and MET are mutated at higher frequency in ER-PR+Her2- cancers than other subsets, suggesting unique biology with potential therapeutic implications. [Table: see text]
Serotype-specific microvascular changes in the liver due to dengue virus (DENV) non-structural protein-1 (NS1)
Authors: J Duruanyanwu, PC Campagnolo, KM Maringer
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): University of Surrey Dengue virus is the most common arbovirus in humans worldwide, with a minor proportion developing severe dengue, which includes the cardiovascular complications of vascular leakage, haemorrhage, organ failure and shock, all of which could prove fatal. The mechanisms that lead to microvascular leakage remain incompletely understood. While DENV-2 NS1 has been shown by our group to disrupt endothelial-pericyte interactions leading to enhanced endothelial cell permeability in vitro, it is unclear whether this is true across all four serotypes of DENV and to what degree. It is also unclear whether DENV NS1 similarly affects all types of pericytes across the body. Our previous work was performed in saphenous venous pericytes, which we here extend to include hepatic stellate cells (HSCs), since the liver is a major site of dengue pathology. In this project, transendothelial electrical resistance readings of co-cultures of endothelial cells with either SVPs or HSCs both revealed the DENV serotypes to significantly lower endothelial membrane function, most notably at DENV-2. Additionally, preliminary data from the 3D Matrigel angiogenesis assay revealed the DENV serotypes to alter the ability of endothelial cells and SVPs to form vascular structures. Interestingly, our alamar blue proliferation assay utilising hepatic stellate cells (HSCs) showed that liver pericytes display increased proliferation in response to the various DENV serotypes, with immunostaining of HSCs also revealing an increase in myofibroblast protein alpha-smooth muscle actin. These results collectively show the ability to disrupt endothelial-pericyte interactions is shared across the DENV serotypes and suggest a potential loss of endothelial-pericyte interaction due to pericyte differentiation in the liver. This information gives further insight to the mechanisms related with DENV interactions with the vasculature, which could aid in establishing a diagnostic test or treatment for those affected with severe dengue fever.
Environmental surveillance of Legionella in tourist facilities of the Balearic Islands, Spain, 2006 to 2010 and 2015 to 2018
Authors: Antonio Doménech-Sánchez, Elena Laso, Clara I Berrocal, Sebastián Albertí
Journal: Eurosurveillance (2022)

BackgroundLegionnaires' disease is a respiratory illness often associated with hotels and travel. Spain is a major tourist destination and one of the European countries with most cases of Legionnaires' disease , both community- and travel-associated. However, the prevalence of Legionella in tourist facilities is unknown.AimThe present investigation aimed to survey the tourist facilities in the Balearic Islands, Spain, for Legionella prevalence.MethodsWe visited tourist facilities in the Balearic Islands in two different periods (2006-2010 and 2015-2018) and took water samples following national and international guidelines. Legionella was investigated by culture methods following international standards (ISO 11731:1998).ResultsWe evaluated 13,472 samples from 465 facilities. Bacteria of the Legionella genus were detected in 65.4% of the surveyed facilities. Contamination of the facilities was significantly higher during the second decade (54.5 vs 78.6%). The most frequent colonisers were L. pneumophila serogroup 2-14. We detected the pathogen in 15.9% and 6.9% of hot and cold water distribution systems samples, respectively. The Legionella contamination rate in cold water systems samples was higher when free chlorine levels were < 0.2 mg/L and at > 25 °C temperatures, while in the hot water systems samples, the contamination rate was higher at < 50 °C. Of the samples from hot tubs, 10.9% were contaminated.ConclusionLegionella prevalence in hotels in the Balearic Islands was high but the contamination rates depended on the installations. Corrective measures are still needed to improve Legionella control.
Association between immune-related adverse events and microbiome composition in patients with advanced non–small cell lung cancer treated with immunotherapy.
Authors: Marion Tonneau, Corentin Richard, Alexis Nolin-Lapalme, Edouard Auclin, Myriam Benlaifaoui, Mayra Ponce, Afnan Al-Saleh, Normand Blais, Marie Florescu, Mustapha Tehfe, Julie Malo, Meriem Messaoudene, Yusuke Okuma, Taiki Hakozaki, Bertrand Routy
Journal: Journal of Clinical Oncology (2022)

9036 Background: Despite immune-checkpoint inhibitors (ICI) achieving high response rates in patients (pts) with advanced non-small cell lung cancer (NSCLC), immune-related adverse events (irAE) remain an important therapeutic hurdle. The gut microbiome represents a novel prognostic marker of ICI response and early clinical evidence suggests that the microbiome may also regulate the development of irAE. We aimed to assess the association between irAE and the gut microbiome composition in advanced NSCLC pts amenable to ICI. Methods: In this study, we enrolled 464 pts from two independent cohorts (Montreal and Tokyo) with advanced NSCLC treated with ICI monotherapy or combination with chemotherapy. Fecal samples were collected prior to ICI initiation. Metagenomics microbiome profiling and 16S rRNA microbiome sequencing were performed for 81 pts and 133 pts respectively. The irAE were classified as CTCEA grade 0-1 (G0-1 irAE) and grade &gt; 2 (G2-5 irAE). Microbiome composition of both groups was represented using alpha diversity, beta diversity indexes and LEfSe relative abundances. Results: Median follow-up was 28.3 months (mos) and the incidence of G2-5 irAE was 25.1% in the Montreal cohort. For the Tokyo cohort, the median follow-up was 19.6 mos and 30.8% pts developed G2-5 irAE. First, in both cohorts, overall survival (OS) and progression-free survival (PFS) were significantly improved for pts with G2-5 irAE compared to G0-1 irAE (OS: HR: 1.71, p = 0.008 and PFS: HR: 1.65, p &lt; 0.001) and (OS: HR: 2.34, p = 0.001, and PFS: HR = 2.34, p = 0.006) respectively. Second, metagenomics analysis of 81 pts demonstrated a numerical decrease of the alpha diversity in terms of observed species in the G2-5 irAE. Dorea sp CAG 31, Anaerosporobacter mobilis, Butyricicococcus, and Enterococcus faecium were overrepresented in pts with G2-5 irAE. Conversely, Gordonibacter was increased in G0-1 irAE. Next, 16S rRNA profiling from the Tokyo cohort revealed an enrichment of Dorea, Butyricicococcus, and Eubacterium ventriosum in G2-5 irAE . Finally, we observed an enrichment in Dorea and Butyricicococcus in the pts with PFS &gt; 6 months, as observed in the G2-5 irAE group. Conclusions: IrAE correlated with clinical outcome and microbiome composition in two independent cohorts of pts with advanced NSCLC. These results prompt further research on the potential mechanism underling the role of the microbiome in the development of irAE.
Oncologic outcomes in patients diagnosed with pT3a non-metastatic renal cell cancer according to renal vein thrombus or fat invasion
Authors: G. Fallara, G. Rosiello, A. Necchi, D. Raggi, W. Cazzaniga, A. Martini, G. Basile, D. Cignoli, G. Colandrea, G. Baiamonte, F. Belladelli, G. Musso, F. Cei, C. Giancristofaro, A. Ieva, D. Canibus, A. Briganti, R. Bertini, F. Montorsi, A. Salonia, A. Larcher, U. Capitanio
Journal: European Urology (2022)
Phase 2 trial of tucatinib plus trastuzumab deruxtecan in patients with HER2+ locally advanced or metastatic breast cancer with and without brain metastases (HER2CLIMB-04, trial in progress).
Authors: Ian E. Krop, Lisa A. Carey, Jorge Ramos, Yiyi Chen, Erika P. Hamilton
Journal: Journal of Clinical Oncology (2022)

TPS1111 Background: Tucatinib is an oral reversible small-molecule tyrosine kinase inhibitor highly selective for human epidermal growth factor receptor 2 (HER2). Tucatinib is approved in the US for use in combination with trastuzumab and capecitabine in adult patients with HER2+ metastatic breast cancer (MBC), with and without brain metastases, who have received ≥1 prior anti–HER2-based regimens in the metastatic setting. Trastuzumab deruxtecan (T-DXd), an antibody–drug conjugate (ADC) comprising a HER2-directed monoclonal antibody conjugated to a topoisomerase I inhibitor payload, is also approved in the US for patients with HER2+ MBC. In HER2+ breast cancer (BC) xenograft models, tucatinib increased the antitumor activity of a HER2-directed ADC comprising a HER2-directed monoclonal antibody conjugated with 8 exatecan moieties (T-Ex) when compared to T-Ex alone (Kulukian et al 2019). While significant advances have been made in the treatment of patients with HER2+ BC, treatment of metastatic disease remains a clinical challenge due to limited treatment options. Methods: HER2CLIMB-04 (NCT04539938) is a single-arm, open-label, multicenter, phase 2 study evaluating the efficacy and safety of tucatinib plus T-DXd in previously treated patients aged ≥18 years with unresectable, locally advanced, or metastatic (LA/M) HER2+ BC. Patients must have prior treatment with a taxane and trastuzumab (with or without pertuzumab) in the LA/M setting or progressed within 6 months after neoadjuvant or adjuvant treatment involving a regimen including a taxane and trastuzumab (with or without pertuzumab). Patients with brain metastases, including active brain metastases, may be enrolled. A safety lead-in portion of the study with 10 patients who were followed for at least 1 cycle has been completed. This portion of the study demonstrated a manageable safety profile so the trial will enroll approximately 60 response-evaluable patients (including the 10 patients from the safety lead-in), evenly distributed between patients with and without brain metastases. The primary endpoint is confirmed objective response rate (cORR) by investigator assessment per RECIST 1.1. Secondary endpoints are progression-free survival (PFS), duration of response (DOR), disease control rate (DCR) by investigator assessment per RECIST 1.1, overall survival, and safety. Exploratory endpoints will include cORR, PFS, DCR, and DOR by independent central review per RECIST 1.1, pharmacokinetic analyses, biomarker analyses, and changes in patient-reported outcomes. Efficacy and safety will be summarized with descriptive statistics. Enrollment in the US began in late 2020. Clinical trial information: NCT04539938.